Abstract
Ischemic brain injury is a widespread pathological condition, the main components of which are a deficiency of oxygen and energy substrates. In recent years, a number of new forms of cell death, including necroptosis, have been described. In necroptosis, a cascade of interactions between the kinases RIPK1 and RIPK3 and the MLKL protein leads to the formation of a specialized death complex called the necrosome, which triggers MLKL-mediated destruction of the cell membrane and necroptotic cell death. Necroptosis probably plays an important role in the development of ischemia/reperfusion injury and can be considered as a potential target for finding methods to correct the disruption of neural networks in ischemic damage. In the present study, we demonstrated that blockade of RIPK1 kinase by Necrostatin-1 preserved the viability of cells in primary hippocampal cultures in an in vitro model of glucose deprivation. The effect of RIPK1 blockade on the bioelectrical and metabolic calcium activity of neuron-glial networks in vitro using calcium imaging and multi-electrode arrays was assessed for the first time. RIPK1 blockade was shown to partially preserve both calcium and bioelectric activity of neuron-glial networks under ischemic factors. However, it should be noted that RIPK1 blockade does not preserve the network parameters of the collective calcium dynamics of neuron-glial networks, despite the maintenance of network bioelectrical activity (the number of bursts and the number of spikes in the bursts). To confirm the data obtained in vitro, we studied the effect of RIPK1 blockade on the resistance of small laboratory animals to in vivo modeling of hypoxia and cerebral ischemia. The use of Necrostatin-1 increases the survival rate of C57BL mice in modeling both acute hypobaric hypoxia and ischemic brain damage.
Highlights
IntroductionPathological cascades, leading to disturbances in the functional and metabolic activity of the brain’s neural networks, develop
Inhibition of Receptor-interacting protein kinase 1 (RIPK1) kinase under normal conditions did not lead to significant changes in the morphology and viability of cells in primary hippocampal cultures (Figure 1)
The effect of the RIPK1 blockade on the viability of neural-network activity of primary nerve-cell cultures in normal conditions and during modeling of ischemic factors was studied
Summary
Pathological cascades, leading to disturbances in the functional and metabolic activity of the brain’s neural networks, develop. It eventually leads to the launch of necrotic and apoptotic processes and the death of structural and functional elements of the neural network [1,2,3]. That hypoxic and ischemic damage are isolated pathologies and often accompany various neurodegenerative diseases, traumatic brain injury, etc. Perinatal hypoxic and ischemic injuries are widespread and among the leading causes of infant mortality and invalidation. Kinases affect energy metabolism (glycogen and glucose utilization) in the cell, participate in the synthesis of coenzymes and nucleotide metabolism, and are the most important components of signaling cascades responsible for maintaining cell viability [4,5,6]
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